Project Summary/Abstract: Cancer Mechanisms (CM) The goal of the Cancer Mechanisms (CM) Program is to elucidate and characterize cellular/molecular pathways that present opportunities to prevent cancer and to improve cancer classification and treatment. The research interests of the program faculty range from fundamental pathway discovery in model organisms, biochemical and cell biological approaches to understanding cell cycle and self-renewal, to elucidation of genetic pathways that present opportunities for improved cancer diagnosis, classification, prevention, and treatment. Furthermore, new members focusing on bioinformatic and proteomic approaches to cancer have enhanced our intra-programmatic and inter-programmatic collaborative opportunities. The CM program currently has 22 members from 9 different departments whose research is organized into several overlapping themes: 1) cell division and cancer, 2) gene expression and cancer, 3) cancer cell biology including, metastasis and vascular biology, and 4) bioinformatic approaches to cancer. Diversity in the research approaches and backgrounds of investigators in the CM program also is accompanied by significant overlap between research themes, with clinical experience and observations informing basic science approaches, and discoveries in biochemical and genetic model systems being translated to clinical trials. The Co-Directors represent both ends of the basic and clinical research spectrum and leverage their diverse experience to enhance collaborations through activities that include recruitment of new members, organizing specialized regional symposia, attracting outside high-profile seminar speakers, and organizing regular programmatic meetings, retreats and ad-hoc technical workshops; with the goal of enhancing members' cancer-oriented research and facilitating collaborative projects. These activities have resulted in a strong collaborative group; as evidenced by the intra-programmatic and inter-programmatic joint grants, cancer clinical trials translating CM science themes, and publications. The program is a generator of discoveries of novel targets, pathways and mechanisms to be studied in the clinic. The success of CM investigators was enabled by the NCCC through the successful strategic recruitment of outstanding new faculty in the Bioinformatics theme (Cheng, Greene), Pathology (Stan), Proteomics (Kettenbach), and in clinical/translational investigations (Dragnev [CE]), the support of shared resources, and the provision of pilot funding. More than 271 cancer-related manuscripts have been published over the reporting period (86 [32%] appearing in high-impact journals), many of them representing intra-program (26=10%) or inter-program (76=28%) collaborations. Intra-programmatic involve all 22 CM program members, with 17 co-authors with other NCCC members, including several other programs, particularly ICI, MT, and CE. Total funding for the program is currently $5.6M, of which $5.4M is peer-reviewed, and $1.8 is from NCI.